Relapse to cocaine-seeking in the animal model of reinstatement is associated with altered glutamate homeostasis in the nucleus accumbens core. Relative to control animals, basal levels of extracellular glutamate are reduced in withdrawal while reinstatement is accompanied by increased glutamate levels. System xc-, which exchanges one extracellular cystine molecule for one intracellular glutamate molecule, has been found to account for the majority of basal extracellular glutamate levels in the nucleus accumbens and its activity is significantly down-regulated after chronic cocaine. The nutritional supplement N-acetylcysteine (NAC) restores the function of the exchanger and basal levels of glutamate. NAC treatment attenuates relapse to cocaine seeking in both animal models and in a human clinical pilot study. Preliminary data presented here demonstrates that glutamate re-uptake, mediated primarily by the glial transporter GLT-1, is also compromised after cocaine self-administration. We propose that akin to restoring glutamate homeostasis with NAC, normalizing glial glutamate transport via GLT-1 up-regulation will inhibit relapse. It is known that beta-lactam antibiotics such as ceftriaxone increase the expression and activity of GLT-1. Experiments within the current proposal are designed to study the co-regulation of system xc- and GLT-1 following cocaine self-administration and treatment with NAC and ceftriaxone. The ability of ceftriaxone to block reuptake and the increase in extracellular glutamate that accompanies it will also be examined. Metabotropic glutamate receptors (mGluRs) are found in the extrasynaptic space and are likely to be influenced by the function of both system xc- and transporters, and current evidence points to the down-regulation of both Group I and II mGluRs in the nucleus accumbens following cocaine self-administration. We will examine the ability of both NAC and ceftriaxone to restore function of group I mGluR in the nucleus accumbens. Completion of the experiments proposed here will further our knowledge regarding the mechanisms by which cocaine addiction alters glutamate homeostasis and mGluR function, and potentially provide further evidence that targeting glutamate transporters is an effective method of treating cocaine relapse. PUBLIC HEALTH RELEVANCE: Cocaine addiction remains a substantial public health problem in the United States today. It is widely recognized that a high risk of relapse exists even after long periods of abstinence and this relapse represents one of the key challenges in the successful treatment of cocaine addiction. This goal of the current proposal, entitled "Striatal Glutamate Homeostasis and Cocaine Relapse," is to test the efficacy of an FDA-approved compound at attenuating relapse in an animal model.